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Training Grant-
Biology of Aging

William Schrage

William G. Schrage

Ph.D., University of Missouri
Professor, Department of Kinesiology

Neural and Vascular Control of Muscle Blood Flow During Exercise or Environmental Stress

Our laboratory aims to understand the integrated control of blood flow in health and disease. We focus on how obesity or pre-diabetes impacts blood flow regulation, in both skeletal muscle and brain tissue. Proper control of blood flow has enormous influence on blood pressure and oxygen delivery-especially during exercise or other environmental stresses. Additionally, limitations in blood flow are often linked to cardiovascular diseases like diabetes, as well as neurodegenerative diseases like dementia. Various state-of-art methods are used to conduct experiments directly in human volunteers.

The primary goal of our research is to determine the causes of disease-related alterations in muscle blood flow or brain blood flow, and the mechanisms responsible. In other words, how do our bodies regulate blood flow, and how does this change with disease?

We are very interested in mechanisms responsible for controlling blood flow, including signals from nerves, contracting muscles, substances in the blood, and the vessels themselves. While much of our research focuses on the cardiovascular response to a single session (acute exercise or hypoxia), we also think about these responses before and after long-term interventions.

Here is a sample of our research questions:

1. What are the body's signals responsible for regulating the "normal" blood flow response to exercise?
2. Do men and women regulate cerebral blood flow (CBF) equally?
3. Does the role of sympathetic adrenergic dilation change in obesity?
4. What is the impact of prediabetes on vascular function, and is this age or gender specific?
5. How does your body increase blood flow when oxygen levels are reduced?

Representative Publications
Kellawan, J. M., Limberg, J. K., Scruggs, Z. M., Nicholson, W. T., Schrage, W. G., Joyner, M. J., & Curry, T. B. (2018). Phosphodiesterase-5 inhibition preserves exercise-onset vasodilator kinetics when NOS activity is reduced. Journal of Applied Physiology, 124(2), 276-282.
View publication via DOI: DOI:10.1152/japplphysiol.00483.2017

Hoscheidt, S. M., Kellawan, J. M., Berman, S. E., Rivera-Rivera L., A., Krause, R. A. Oh, J. M., . . . Asthana, S., Johnson, S. C., Schrage, W. G., & Bendlin, B. B. (2017). Insulin resistance is associated with lower arterial blood flow and reduced cortical perfusion in cognitively asymptomatic middle-aged adults. Journal of Cerebral Blood Flow and Metabolism, 37(6), 2249-2261.
View publication via DOI: DOI:10.1177/0271678X16663214

Limberg, J. K., Malterer, K. R., Mikhail Kellawan, J., Schrage, W. G., Wilkins, B. W., Nicholson, W. T., ... Curry, T. B. (2017). Potentiation of the NO-cGMP pathway and blood flow responses during dynamic exercise in healthy humans. European Journal of Applied Physiology, 117(2), 237-246.
View publication via DOI: DOI:10.1007/s00421-016-3523-7

Mikhail Kellawan, J., Harrell, J. W., Roldan-Alzate, A., Wieben, O., & Schrage, W. G. (2017). Regional hypoxic cerebral vasodilation facilitated by diameter changes primarily in anterior versus posterior circulation. Journal of Cerebral Blood Flow and Metabolism, 37(6), 2025-2034.
View publication via DOI: DOI:10.1177/0271678x16659497

Kellawan, J. M., Harrell, J. W., Schrauben, E. M., Hoffman, C. A., Roldan-Alzate, A., Schrage, W. G., & Wieben, O. (2016). Quantitative cerebrovascular 4D flow MRI at rest and during hypercapnia challenge. Magnetic Resonance Imaging, 34(4), 422-428.
View publication via DOI: DOI:10.1016/j.mri.2015.12.016

Kellawan, J. M., Johansson, R. E., Harrell, J. W., Sebranek, J. J., Walker, B. J., Eldridge, M. W., & Schrage, W. G. (2015). Exercise vasodilation is greater in women: Contributions of nitric oxide synthase and cyclooxygenase. European Journal of Applied Physiology, 115(8), 1735-1746.
View publication via DOI: DOI:10.1007/s00421-015-3160-6

Peltonen, G. L., Harrell, J. W., Rousseau, C. L., Ernst, B. S., Marino, M. L., Crain, M. K., & Schrage, W. G. (2015). Cerebrovascular regulation in men and women: Stimulus-specific role of cyclooxygenase. Physiological Reports, 3(7).
View publication via DOI: DOI:10.14814/phy2.12451

Du, S., Joyner, M. J., Curry, T. B., Eisenach, J. H., Johnson, C. P., Schrage, W. G., & Jensen, M. D. (2014). Effect of beta2-adrenergic receptor polymorphisms on epinephrine and exercise-stimulated lipolysis in humans. Physiological Reports, 2(5), e12017.
View publication via DOI: DOI:10.14814/phy2.12017

Harrell, J. W., & Schrage, W. G. (2014). Cyclooxygenase-derived vasoconstriction restrains hypoxia-mediated cerebral vasodilation in young adults with metabolic syndrome. American Journal of Physiology. Heart and Circulatory Physiology, 306(2), H261-269 .
View publication via DOI: DOI:10.1152/ajpheart.00709.2013

Limberg, J. K., Kellawan, J. M., Harrell, J. W., Johansson, R. E., Eldridge, M. W., Proctor, L. T., Sebranek, J. J., & Schrage, W. G. (2014). Exercise-mediated vasodilation in human obesity and metabolic syndrome: Effect of acute ascorbic acid infusion. American Journal of Physiology. Heart and Circulatory Physiology, 307(6), H840-847.
View publication via DOI: DOI:10.1152/ajpheart.00312.2014

Limberg, J. K., Morgan, B. J., Sebranek, J. J., Proctor, L. T., Eldridge, M. W., & Schrage, W. G. (2014). Neural control of blood flow during exercise in human metabolic syndrome. Experimental Physiology, 99(9), 1191-1202.
View publication via DOI: DOI:10.1113/expphysiol.2014.078048

Limberg, J. K., Morgan, B. J., Schrage, W. G., & Dempsey, J. A. (2013). Respiratory influences on muscle sympathetic nerve activity and vascular conductance in the steady state. .American Journal of Physiology. Heart and Circulatory Physiology, 304(12), H1615-1623.
View publication via DOI: DOI:10.1152/ajpheart.00112.2013

Limberg, J. K., Johansson, R. E., McBride, P. E., & Schrage, W. G. (2013). Increased leg blood flow and improved femoral artery shear patterns in metabolic syndrome after a diet and exercise programme. Clinical Physiology and Functional Imaging, 34(4), 282-289.
View publication via DOI: DOI:10.1111/cpf.12095

Limberg, J.K., Evans, T.D., Blain, G.M., Pegelow, D.F., Danielson, J.R., Eldridge, M.W., ... Schrage, W.G. (2012). Effect of obesity and metabolic syndrome on hypoxic vasodilation. European Journal of Applied Physiology, 112(2), 699-709.
View publication via DOI: DOI:10.1007/s00421-011-2025-x

Limberg, J,K., Evans, T.D., Pegelow, D.F., Danielson, J.R., Eldridge, M.W., Procor, L.T., Sebranek, J.J., & Schrage, W.G. (2012). Heterogeneous Vascular Responses to Hypoxic Forearm Exercise in Young and Older Adults. European Journal of Applied Physiology, 112(8), 3087-3095.
View publication via DOI: DOI:10.1007/s00421-011-2280-x

Harrell, J,W., Morgan, B.J., & Schrage, W.G. (2012). Impaired hypoxic cerebral vasodilation in younger adults with metabolic syndrome. Diabetes and Vascular Disease Research, 0(0), 1-8.
View publication via DOI: DOI:10.1177/1479164112448875

Blain, G. M., Limberg, J. K., Mortensen, G. F., & Schrage, W. G. (2012). Rapid onset vasodilatation is blunted in obese humans. Acta Physiologica, 205(1), 103-112.
View publication via DOI: DOI:10.1111/j.1748-1716.2011.02370.x

Limberg, J. K., Evans, T. D., Blain, G. M., Pegelow, D. F., Danielson, J. R., Eldridge, M. W., . . . Schrage, W. G. (2012). Effect of obesity and metabolic syndrome on hypoxic vasodilation. European Journal of Applied Physiology, 112(2), 699-709.
View publication via DOI: DOI:10.1007/s00421-011-2025-x

Limberg, J. K., Morgan, B. J., Sebranek, J. J., Proctor, L. T., Walker, B. J., Eldridge, M. W., & Schrage, W. G. (2012). Altered neurovascular control of the resting circulation in human metabolic syndrome. The Journal of Physiology, 590(Pt 23), 6109-6119.
View publication via DOI: DOI:10.1113/jphysiol.2012.239780

Limberg, J.K., & Schrage, W.G. (2011). Hypoxia: Just say NO? Journal of Physiology, 589(9), 2111-2.
View publication via DOI: DOI:10.1113/jphysiol.2011.209007

Limberg, J.K., De Vita, M.D., Blain, G.M., & Schrage, W.G. (2010). Muscle blood flow responses to dynamic exercise in young obese humans. Journal of Applied Physiology, 108(2), 349-355.
Click here to download this publication.
View publication via DOI: DOI:10.1152/japplphysiol.00551.2009

Limberg, J.K., Eldridge, M.W., Proctor, L.T., Sebranek, J.J., & Schrage, W.G. (2010). Alpha-Adrenergic Control of Blood Flow during Exercise: Effect of Sex and Menstrual Phase. Journal of Applied Physiology, 109(5), 1360-68.
View publication via DOI: DOI:10.1152/japplphysiol.00518.2010

Kirby, B.S., Voyles, W.F., Simpson, C.B., Carlson, R.E., Schrage, W.G., & Dinenno, F.A. (2009). Endothelium-dependent vasodilatation and exercise hyperaemia in ageing humans: Impact of acute ascorbic acid administration. Journal of Physiology, 587(9), 1989-2003.
View publication via DOI: DOI:10.1113/jphysiol.2008.167320

Schrage, W.G. (2008). Not a search in vein: Novel stimulus for vascular dysfunction after simulated microgravity. J. Appl. Physiology, 104, 1257-1258. PMID: 1827690.
View publication via DOI: DOI:10.​1152/​japplphysiol.​00174.​2008

Ji, L.L., Diffee, G., & Schrage, W. (2008). Challenges in exercise physiology research and education. Quest, 60, 13-18.

Basu, A., Charkoudian, N., Schrage, W.G., Rizza, R.A., Basu, R., & Joyner, M.J. (2007). Beneficial effects of Glucagon-like peptide-1 (GLP-1) on endothelial function in humans: Dampening by Glyburide but not by Glimepiride. Am. J. Physiol. Endocrinol. Metab., 293(5), 289-95. PMID: 1771199.
View publication via DOI: DOI:10.​1152/​ajpendo.​00373.​2007

Masuki, S., Eisenach, J.H., Schrage, W.G., Dietz, N.M., Johnson, C.P., Wilkins, B.W., Dierkhising, R.A., Sandroni, P., Low, P.A., & Joyner, M.J. (2007). Arterial baroreflex control of heart rate during exercise in postural tachycardia syndrome. J. Appl. Physiology, 103(4), 1136-42. PMID: 1767356.
View publication via DOI: DOI:10.​1152/​japplphysiol.​00176.​2007

Masuki, S., Eisenach, J.H., Schrage, W.G., Johnson, C.P., Dietz, N.M., Wilkins, B.M., Sandroni, P., Low, P.A., & Joyner, M.A. (2007). Reduced stroke volume during exercise in postural tachycardia syndrome. J. Appl. Physiology, 103(4), 1128-35. PMID: 176268.
View publication via DOI: DOI:10.​1152/​japplphysiol.​00175.​2007

Schrage, W.G., Eisenach, J.H., & Joyner, M.J. (2007). Aging reduces nitric oxide and prostaglandin mediated vasodilation during exercise. J. Physiol., 579(1), 227-36. PMID:17138603.
View publication via DOI: DOI:10.1113/jphysiol.2006.124313

Wilkins, B.W., Schrage, W.G., Liu, Z., Hancock, K.C., Joyner, M.J. (2006). Systemic hypoxia and vasoconstrictor responsiveness in exercising human muscle. J. Appl. Physiology, 101(5), 1343-50. PMID: 16809628.
View publication via DOI: DOI:10.1152/japplphysiol.00487.2006

Eisenach, J.H., Schroeder, D.R., Pike, T.L., Johnson, C.P., Schrage, W.G., Snyder, B.M., Johnson, B.D., Turner, S.T., & Joyner, M.J. (2006). Dietary sodium restriction and beta2-adrenergic receptor polymorphism modulate cardiovascular function in humans. J. Physiol., 574(3), 955-65. PMID: 16740612.

Schrage, W.G., Dietz, N.M., & Joyner, M.J. (2006). Effects of combined inhibition of ATP-sensitive potassium channels, nitric oxide and prostaglandins on hyperemia during moderate exercise. J. Appl. Physiology, 100(5), 1506-12. PMID: 16469932.
View publication via DOI: DOI:10.​1152/​japplphysiol.​01639.​2005

Schrage, W.G., Wilkins, B.W., Dean, V.L., Scott, J.P., Henry, J.K., Wylam, M.E., Joyner, M.J. (2005). Exercise hyperemia and vasoconstrictor responses in humans with cystic fibrosis. J. Appl. Physiology, (99), 1866-1871.
View publication via DOI: DOI:10.​1152/​japplphysiol.​00616.​2005

Schrage, W.G., Eisenach, J.E., Dietz, N.M., & Joyner, M.J. (2005). Agonist-dependent variability of contributions of nitric oxide and prostaglandins in human skeletal muscle. J. Appl. Physiology, 98(4), 1251-1257.
View publication via DOI: DOI:10.​1152/​japplphysiol.​00966.​2004

Schrage, W.G., Eisenach, J.E., Dinenno, F.A., Sandroni, P., Low, P.A., & Joyner, M.J. (2004). Effects of midodrine on exercise-induced hypotension and blood pressure recovery in autonomic failure. J. Appl. Physiol., 97(5), 1978-1984.
View publication via DOI: DOI:10.​1152/​japplphysiol.​00547.​2004

Schrage, W.G., Joyner, M.J., & Dinenno, F.A. (2004). Local inhibition of nitric oxide and prostaglandins independently reduces forearm exercise hyperaemia in humans. J. Physiol., 557(2), 599-611.
View publication via DOI: DOI:10.1113/jphysiol.2004.061283

Laughlin, M.H., Turk, J., Schrage, W.G., Woodman, C.R., & Price, E.M. (2003). Influence of coronary artery diameter on eNOS protein content. Am. J. Physiol., Heart, 284(4), H1307-1312.
View publication via DOI: DOI:10.​1152/​ajpheart.​00792.​2002

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